Implications of RAS Mutational Status in Subsets of Patients With Newly Diagnosed Acute Myeloid Leukemia Across Therapy Subtypes

Authors

Daniel Rivera
Kunhwa Kim
Rashmi Kanagal-Shamanna
Gautam Borthakur
Guillermo Montalban-Bravo
Naval Daver
Courtney Dinardo
Nicholas J Short
Musa Yilmaz
Naveen Pemmaraju
Koichi Takahashi
Elias J Jabbour
Sherry Pierce
Marina Konopleva
Kapil Bhalla
Guillermo Garcia-Manero
Farhad Ravandi
Hagop Kantarjian
Tapan M Kadia

Publication Date

12-1-2022

Journal

American Journal of Hematology

Abstract

Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with RAS-mut, favorable karyotype and concomitant NPM1 mutations were associated with a higher CR/CRi rate, OR 23.2 (95% CI: 2.7-192.7; p < .001) and OR 2.8 (95% CI: 1.1-6.9; p = .02), respectively, while secondary and treated secondary (ts)-AML were associated with low response rates, OR 0.34 (95% CI: 0.1-0.9; p = .04) and OR 0.22 (95% CI: 0.09-0.5; p = .001), respectively. Intensive chemotherapy was associated with high response rates OR 5.9 (95% CI: 2.9-12.2; p < .001). Better median OS was observed among those with favorable karyotype, HR 0.28 (95% CI: 0.1-0.6; p = .002), and those treated with intensive chemotherapy, HR 0.42 (95% CI: 0.2-0.6 p < .001). Conversely, ts- AML and co-occurrence of mutations in TP53 were associated with poor median OS; HR 2.3 (95% CI: 1.4-3.9; p = .001) and HR 1.7 (95% CI: 0.9-3.1; p = .06), respectively. The addition of venetoclax was associated with a non-significant improvement in CR/CRi and OS.

Keywords

Humans, fms-Like Tyrosine Kinase 3, Genes, ras, Karyotype, Leukemia, Myeloid, Acute, Mutation, Prognosis, ras Proteins, Acute Myeloid Leukemia, RAS mutation, AML therapies

DOI

10.1002/ajh.26731

PMID

36117258

PMCID

PMC11975417

PubMedCentral® Posted Date

4-7-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes